This application is a 371 of PCT/EP97/05426 filed Oct. 2, 1997.
The present invention relates to preparation of new corticoid compounds.
In particular it relates to steroid-structured compounds having anti-inflammatory, immunodepressive and angiostatic activities (the so-called steroid anti-inflammatory drugs).
The compounds according to the present invention are therapeutically useful in the treatment of pathologic conditions where generally corticosteroid (corticoids) preparations are used, but with increased benefits.
This represents an unexpected advantage over the known corticoids products. In fact, by taking into account the various defined therapeutic uses of a specific product, it is always possible, with the new products of the present invention, to find a better combination of results with respect to the known corticoids. Contrary to any expectation the products of the present invention are characterised by the fact that they show an improved therapeutic profile: high activity combined with low side-effects.
Corticoids are well known as a first-choice pharmacological measure in the treatment of inflammatory disease. Drugs in this categoryxe2x80x94which include, for example, hydrocortisone, cortisone, prednisolone, prednisone, fludrocortisone, desoxycorticosterone, methylprednisolone, triamcinolone, paramethasone, betametasone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, beclomethasone, acetoxypregnelone, etc.xe2x80x94have marked pharmacotoxicological effects on various organs. Because of this, the clinical use and discontinued use thereof cause a series of side effects some of which are very severe. See for example Goodman and Gilman: xe2x80x9cThe Pharmaceutical Basis of Therapeuticsxe2x80x9d, 9th Ed., pages 1459-1465, 1996.
These toxic effects include:
those on bone which lead to changed cell metabolism and a high frequency of osteoporosis;
those on the cardiovascular system which cause hypertensive reactions;
those on the gastrointestinal tract which cause gastric damage.
See for instance Martindale: xe2x80x9cThe Extrapharmacopoeiaxe2x80x9d, 30th Ed., pages 712-723, 1993.
According to the above mentioned art it appears to be almost impossible for therapeutic activities to be separated from side effects, see Goodman et al., as mentioned above, at page 1474.
Known in the art are non-steroid anti-inflammatory drugs either with or without acidic ending see patents WO 94/04484, WO 94/12463, WO 95/09831, WO 95/30641 for non-acidic ending and the patents therein mentioned for those with acidic ending.
DE-A-2222491 (1) discloses pregnane derivatives having at position 21 the group 
Said compounds are said to be endowed of antiinflammatory, antiallergic and cardiotropic activity. The single compounds are vasodilators.
U.S. Pat. No. 3,494,941 (2) discloses steroid derivatives from estrane-3-ol or estr-4-en-3-one useful as vasodilators in the treatment of heart conditions, such as coronary insufficiency and angina pectoris. Said compounds have at position 17 an ether linker attached to a nitrate radical. Nitrate groups can be also at positions 3 and 16 of the steroid ring.
Arzneimittel Forschung, vol. 19, n. 4, 1969, pp. 584-685 (3) discloses 3- and 17-nitrate ester of androstane derivatives, 3, a 17-dinitrate derivative of androstene, 17-nitrate esters of testosterone derivatives and 21-nitrate esters derivatives of desoxicortisone, cortisone and prednisone. In the paper it is stated that desoxicorticosterone nitrate promotes protein anabolism in different organs.
WO-A-97/34871 (4) discloses (i) compounds comprising a steroid, a xcex2-agonist, an anticholinergic, a mast cell stabilizer or a PDE (phosphodiesterase) inhibitor to which is directly or indirectly linked at least one NO or NO2 group or a group which stimulates the endogenous production of NO or EDRF (endothelium-derived relaxing factor) in vivo, said group linked through sites such as oxygen, sulfur, carbon and nitrogen; (ii) compositions comprising a therapeutically effective amount of a steroid, a xcex2-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor, optionally substituted with at least one NO or NO2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, in combination with a compound that donates, transfers, or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF in vivo.
However, it should be toted that steroid compounds are completely different from non-steroid compounds chemically, pharmacologically and biochemically as the pharmaco-toxicological mechanism of action of non-steroid products is based on inhibition of one or more cyclo-oxvgenases (COX), while steroid products have nothing to share with COX and have more complex pharmaco-toxicological mechanisms of action which have not yet been fully explained.
It is well known that these two groups of compounds are listed in completely separate categories in international pharmacopoeias.
The applicant has surprisingly and unexpectedly found corticosteroids (corticoids) which are very effective, even superior to those in the known art, and have, at the same time, a higher tolerance than the known corticoids as unexpectedly they do not cause the above side effects, or when they do, these are lower.
An object of the present invention are corticosteroids and their use as anti-inflammatory, immunosuppressive and angiostatic agents having the general formula:
Bxe2x80x94X1xe2x80x94NO2
or their esters or salts, where:
B has the following structure: 
where, in place of the hydrogens H in the CH group or two hydrogens H2 in the CH2 group shown in the general formula, there may be the following substituents:
at position 1-2: there may be a double bond;
at position 2-3: there may be the following substituent: 
at position 2: there may be Cl, Br;
at position 3: there may be CO, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Cl, OH;
at position 4-5: there may be a double bond;
at position 5-6: there may be a double bond;
at position 6: there may be Cl, F, CH3, xe2x80x94CHO;
at positicn 7: there may be Cl;
at position 9: there may be Cl, F;
at position 11: there may be OH, CO, Cl;
at position 16, there may be CH3, OH, xe2x95x90CH2;
at position 17: there may be OH, CH3, OCO(O)ua(CH2)vaCH3, or 
where ua is an integer equal to 0 or 1, va is an integer from 0 to 4;
at positions 16-17: there may be the following groups 
R and Rxe2x80x2 are eaual or different one from the other and may be hydrogen or linear or branched alkyls having from 1 to 4 carbon atoms, preferably R=Rxe2x80x2=CH3;
B being a carticasteraid residue;
(1) when at position 9 there is F, at position 11 there is OH, at positions 1-2 and at positions 4-5 there are two double bonds, at positions 3 and 20 two groups CO, at positions 16 and 17 there cannot be the group: 
Rxe2x80x3 is xe2x80x94(COxe2x80x94L)txe2x80x94(X)t1xe2x80x94
where t and t1 are integers equal to 1; the bivalent bridging group L is selected from:
(CR4R5)na(O)nb(CR4R5)nxe2x80x2a(CO)nxe2x80x2b(O)nxe2x80x3b(CO)nxe2x80x2xe2x80x3b(CR4R5)nxe2x80x3a
where na, nxe2x80x2a and nxe2x80x3a are equal or different one from the other and are integers from 0 to 6, preferably from 1 to 3; nb, nbxe2x80x2, nxe2x80x3b and nxe2x80x2xe2x80x3b are equal or different one from the other and are integers eorual to 0 or 1; R4 and R5 are equal or different one from the other and are chosen from H, linear or branched alkyl having from 1 to 5 carbon atoms, preferably from 1 to 3;
X is equal to X0=0, NH, NR1C where R1C is a linear or branched alkyl having from 1 to 10 C atoms;
X1 is a bivalent connecting bridge chosen from:
YO
where Y is a linear or whenever possible branched C1-C20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms;
Y1 selected from 
where n3 is an integer from 0 to 3; 
where nfxe2x80x2 is an integer from 1 to 6, preferably from 2 to 4; 
where R1fxe2x95x90H, CH3 and nf is an integer from 1 to 6, preferably from 2 to 4.
The compounds which can be mentioned, and which are those preferred, are the ones listed below where B can be obtained according to the known processes of the art.
For example, the precursors and related processes described for example in The Merck Index, 12th Ed. of 1996, herein incorporated by reference, can be mentioned as precursors and related processes. The precursors (according to the Merck nomenclature) include the following, where H2, H, R, Rxe2x80x2, Rxe2x80x3 have the meaning as defined in the compounds listed below: budesonide, hydrocortisone, alclometasone, algestone, beclomethasone, betamethasone, chloroprednisone, clobetasol, clobetasone, clocortolone, cloprednol, cortisone, corticosterone, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluazacort, flucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortyn butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hydrocortamate, loteprednol etabonate, medrysone, meprednisone, methylprednisolone, mometasone furoate, parametasone, prednicarbate, prednisolone, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, triamcinolone, 21-acetoxypregnenolone, cortivazol, amcinonide, fluticasone procriorate, maziporedon, tixocortol, triamcinolone hexacetonide.
The X1 connecting bridges as above defined are obtainable by using the methods known in the art as indicated above or by modifing the known methods by introducing X1 bridges when these are different from the connecting bridges described in the listed patents, using processes known in the art. Generally the connection between B and X1 is, as seen, of an ester or amide type (NH or NR1C, as defined in X). Any well known synthetic route for forming these bonds can be used to form this connection.
In the case of esters, the most direct synthethic route includes:
reaction of acyl chlorides Bxe2x80x94COxe2x80x94Cl in halogen alcohols of the HOxe2x80x94Yaxe2x80x94Cl, HOxe2x80x94Yaxe2x80x94Br, HOxe2x80x94Yaxe2x80x94I-type, where Ya is equal to Y or Y1 without the oxygen atom, in test conditions which are part of the known art.
The reaction products of formula Bxe2x80x94COxe2x80x94Oxe2x80x94Yxe2x80x94Cl(Br,I) can also be obtained by reacting the sodium or potassium salts of salts acids Bxe2x80x94COxe2x80x94OH with dihalogen derivatives of the general formula YaCl2, YaBra or YaI2, ClYaBr, ClYaI, BrYaI.
The reaction products are converted into the final products by reacting with AgNO3 in acetonitrile according to what is known in the literature.
The general scheme is as follows:
Bxe2x80x94COxe2x80x94Cl+HOxe2x80x94Yaxe2x80x94Brxe2x86x92Bxe2x80x94COxe2x80x94Oxe2x80x94Yaxe2x80x94Br+AgNO3xe2x86x92Bxe2x80x94X1NO2
where X1=YaO.
The general scheme may also be as follows:
Bxe2x80x94COxe2x80x94ONa+Br2Yaxe2x86x92Bxe2x80x94COxe2x80x94Oxe2x80x94Yaxe2x80x94Br+AgNO3xe2x86x92Bxe2x80x94X1NO2
where X1=YaO.
In this case of amide, the synthetic sequence includes reaction of the same acyl chlorides BCOCl with aminoalcohols of the general formula NH2xe2x80x94Yaxe2x80x94OH, NHR1Cxe2x80x94Yaxe2x80x94OH to give amides of the general formula:
Bxe2x80x94COxe2x80x94NHxe2x80x94Yaxe2x80x94OH and Bxe2x80x94COxe2x80x94NR1Cxe2x80x94Yaxe2x80x94OH
according to known methods.
Reaction of these amides with halogenating agents such as, for example PCl5, PBr3, SOCl2, etc., gives the halogen derivatives of the general formula:
Bxe2x80x94COxe2x80x94NHxe2x80x94Yaxe2x80x94Br(Cl) and Bxe2x80x94COxe2x80x94NR1Cxe2x80x94Yaxe2x80x94Br(Cl).
The latter give the final products BX1NO2 by reacting with AgNO3 in acetonitrile according to methods known in the literature.
The sequence may be represented as: 
where YaO is X1.
An alternative route to ester formation is reaction of the sodium or potassium salts of the acids with the nitric esters of halogen alcohols of the general formula:
NO2xe2x80x94Oxe2x80x94Yaxe2x80x94Cl(Br, I)
to directly give the products of the invention.
The reaction scheme is as follows:
Bxe2x80x94COxe2x80x94ONa+Brxe2x80x94Yaxe2x80x94ONO2xe2x86x92Bxe2x80x94COxe2x80x94Oxe2x80x94Yaxe2x80x94ONO2
where YaO is X1.
Other synthetic routes similar to those described above include those in which the dihalogen derivative Br2Ya is reacted with enolates. The reaction products are then converted by reacting with AgNO3 in acetonitrile according to the above reaction. The general scheme is shown for an xe2x80x94OH in group B, of the type xe2x80x94CH2xe2x80x94OH, xe2x95x90CHxe2x80x94OH, is as follows: 
The processes to obtain these X1 connecting groups are described in patent application WO95/30641 herein incorporated by reference.
As said above the compounds of the invention of formula Bxe2x80x94X1xe2x80x94NO2 or their pharmaceutical compositions, are used for the treatment of diseases in which the well known corticoids products are employed.
In particular, it can be specifically mentioned the use in respiratory disorders, e.g. antiasthmatic, the use as antiarthritic, antipruritic, antipsoriatic, antieczematic; the use in vascular disorders, e.g. as angiostatic, the use in immunology disorders, e.g. as immunosoppressive.
The compounds, or their compositions, of the present invention can be administered for example by oral, rectal (intestinal disorders), parenteral route or by local (dermal, topical, transdermal, ocular, inhalatory, etc.) application.